Date: {{$ActivityAssignDate}}

Dear Dr. {{ $doctorName }},


Subject : An observational cross-sectional survey study to understand the clinician approach to up dosing of anti-histaminic agents in management of AR.


Allergic rhinitis (AR) is a prevalent chronic condition characterized by nasal congestion, rhinorrhoea, sneezing, and nasal itching, which significantly impacts the quality of life. It affects up to 40% of the global population and is commonly associated with comorbidities such as asthma and sinusitis (1).


The standard pharmacologic treatment for AR includes oral antihistamines, intranasal corticosteroids, and leukotriene receptor antagonists. Second-generation antihistamines (SGAHs) are preferred over first-generation antihistamines (FGAHs) due to their reduced sedative effects and better safety profile (2). However, not all patients achieve adequate symptom control with standard doses, leading to the concept of up-dosing, where antihistamines are administered at higher doses than typically recommended.


There is an unmet need understand the rationale, efficacy, safety, and clinical implications of antihistamine up-dosing in AR management.


Rationale for Up-Dosing


SGAHs, such as levocetirizine, fexofenadine, bilastine, and desloratadine, primarily exert their effect by blocking histamine H1 receptors. Despite their high receptor affinity, some AR patients exhibit suboptimal responses to standard doses, particularly in severe or refractory cases (3). The **ARIA (Allergic Rhinitis and its Impact on Asthma) guidelines** suggest that non-sedating antihistamines may be up-dosed to improve efficacy without significantly increasing adverse effects (4). The underlying rationale for up-dosing includes:


- Inter-individual variability in drug metabolism**: Some patients metabolize antihistamines faster, reducing their efficacy at standard doses.


- Severe histamine-mediated symptoms**: Increased histamine release in severe AR may require higher antihistamine concentrations for adequate blockade.


- Pharmacokinetic considerations**: Some antihistamines, such as fexofenadine, exhibit dose- proportional increases in plasma concentration, allowing for potential up-dosing without exceeding safety thresholds (5). Several clinical trials and real-world studies support the practice of up-dosing SGAHs in AR:


Fexofenadine Up-Dosing:


Fexofenadine, a highly selective H1 receptor antagonist, is often considered for up-dosing due to its favourable safety profile. Studies have shown that increasing the dose from 120 mg to 240 mg daily enhances symptom control without significant adverse effects (6). In a randomized controlled trial (RCT), Day et al. found that up-dosing fexofenadine 240 mg was significantly more effective in reducing total nasal symptom scores (TNSS) compared to standard doses, with minimal sedation or cardiac effects (7).


Levocetirizine and Desloratadine Up-Dosing:


Levocetirizine and desloratadine have been investigated at doses two to four times** higher than standard recommendations. Kuna et al. demonstrated that levocetirizine 10 mg daily provided better symptom relief than the 5 mg standard dose, particularly in severe AR cases (8). Similarly, Horak et al. found that desloratadine 10 mg daily was more effective than 5 mg in controlling nasal congestion and sneezing, without notable adverse effects (9).


Bilastine Up-Dosing:


Bilastine, a newer SGAH with a high safety margin, has also been evaluated for up-dosing. A study by Worm et al. reported that bilastine 40 mg daily (double the recommended dose) improved symptom relief in persistent and severe AR patients who did not respond adequately to 20 mg, with no increase in sedation or QT prolongation (10).


Safety Considerations


While up-dosing SGAHs appears beneficial, safety remains a key concern. Unlike FGAHs, which can cause sedation, anticholinergic effects, and cardiotoxicity at high doses, SGAHs generally have a wider therapeutic index. However, potential risks include:


- Cardiac effects: Although rare, QT prolongation has been reported with terfenadine and astemizole, leading to their withdrawal (11).


Current SGAHs, including fexofenadine and bilastine, have minimal cardiac effects even at high doses.


Guidelines and Clinical Recommendations


The ARIA guidelines acknowledge antihistamine up-dosing as a potential strategy in AR management, particularly for moderate-to-severe cases unresponsive to standard doses (4).


Up-dosing of antihistamines is an emerging strategy in the management of allergic rhinitis, providing enhanced symptom relief in patients unresponsive to standard doses. Clinical evidence supports the efficacy and safety of up-dosing second-generation antihistamines, particularly fexofenadine, levocetirizine, desloratadine, and bilastine. While safety concerns remain minimal, patient selection and careful monitoring are essential to optimizing therapeutic outcomes. Further research is warranted to establish standardized guidelines and long-term safety data for antihistamine up-dosing. Hence this survey is designed to understand the clinician approach to uprising of anti-histaminic agents in management of AR.


We trust you and we are partners in providing safe and effective drug therapy. In that spirit, we hope you will consent to participate in this study. If you do, please sign and return the enclosed reply along with your visiting card for the accuracy of records.

Yours truly,

Mr. Sandeep Sharma

Vice President -Sales and Marketing

Sun Pharmaceutical Laboratories Limited

References


1. Bousquet J, Khaltaev N, Cruz AA, et al. Allergic Rhinitis and its Impact on Asthma (ARIA) 2008 update. Allergy. 2008;63(Suppl 86):8-160.


2. Canonica GW, Bousquet J, Mullol J, et al. A survey of the burden of allergic rhinitis in Europe. Allergy. 2007;62(1):17-25.


3. Ciprandi G, Cirillo I. The lower airway pathology of rhinitis. J Allergy Clin Immunol. 2006;118(5):1105-9.

4. Bousquet J, Schünemann HJ, Togias A, et al. Next-generation ARIA care pathways for rhinitis and asthma: A Model for multimorbid chronic diseases. Clin Transl Allergy. 2019;9(1):44.


5. Berger WE. Overview of allergic rhinitis. Ann Allergy Asthma Immunol. 2003;90(6 Suppl 3):7-12.


6. Bachert C, Bousquet J, Canonica GW, et al. Levocetirizine improves quality of life and reduces costs in persistent allergic rhinitis. Allergy. 2008;63(8):920-6.


7. Day JH, Briscoe MP, Rafeiro E, et al. Comparative efficacy of fexofenadine 240 mg, loratadine 10 mg, and placebo in seasonal allergic rhinitis. Ann Allergy Asthma Immunol. 1997;79(5):443-8.


8. Kuna P, Bachert C, Nowacki Z, et al. Efficacy and safety of levocetirizine in seasonal allergic rhinitis. Allergy. 2007;62(9):968-75.


9. Horak F, Stübner UP, Zieglmayer R, et al. Effectiveness of high-dose desloratadine in persistent allergic rhinitis. J Allergy Clin Immunol. 2009;124(3):569-75.


10. Worm M, Horak F, Klimek L, et al. Efficacy and safety of bilastine 40 mg in patients with allergic rhinitis. Clin Drug Investig. 2010;30(2):109-17.


11. Simons FE. H1-antihistamines: current status and future directions. World Allergy Organ J. 2011;4(9):29-33.